Transcriptional regulation and therapeutic modulation of cytotoxic function in tumour-infiltrating CD4+ T cells

免疫系统可能掌握着抗击癌症的关键。最近的癌症免疫治疗方法一直集中在增强或重新激活细胞毒性CD8+T细胞功能。然而，对治疗没有反应的患者比例仍然很高，一些肿瘤不是CD8+T细胞的靶点。越来越多的人认识到，CD4+T辅助细胞也可以获得细胞毒效应功能，这些细胞构成了对癌症和病毒感染反应的关键组成部分。然而，我们对细胞毒性CD4+T细胞来源和功能的了解明显落后于CD8+T细胞和其他CD4+T细胞系。识别调节细胞毒性CD4+T细胞分化和功能的因素将为增强对癌症和病毒感染的免疫反应提供新的机会。我们建议结合基因组学和癌症免疫学的方法来识别控制肿瘤中细胞毒CD4+T细胞的分化和功能的调节蛋白，以及如何针对这些机制来控制这些细胞的活性。在我们实验室以前工作的基础上，我们将使用转基因的肿瘤模型来识别转录调控因子控制细胞毒CD4+T细胞前体分化的基因。我们还将确定检查点的性质，该检查点防止未经治疗的肿瘤中的前体细胞获得细胞毒功能。最后，我们将确定这些调节机制是否可以有针对性地促进细胞毒性CD4+T细胞功能和肿瘤免疫。这项工作将提供控制细胞毒性CD4+T细胞功能的因素的知识，并确定可以在患者身上利用这些细胞的活性的靶点。

The immune system may hold the key to combating cancer. Recent cancer immunotherapy approaches have been focused on boosting or re-invigorating cytotoxic CD8+ T cell function. However, the proportion of patients that do not respond to therapy remains high and some tumours are not targeted by CD8+ T cells. There is growing recognition that CD4+ T helper cells can also acquire cytotoxic effector function, and that these cells form a key component of the response to cancer and viral infection. However, our understanding of cytotoxic CD4+ T cell derivation and function lags significantly behind that of their CD8+ counterparts and other CD4+ T cell lineages. Identifying factors that regulate the differentiation and function of cytotoxic CD4+ T cells would provide new opportunities to boost the immune response to cancer and viral infection. We propose to combine genomics and cancer immunology approaches to identify regulatory proteins that control the differentiation and function of cytotoxic CD4+ T cells in tumours and how these mechanisms may be targeted to harness the activity of these cells.Building on previous work from our labs, we will use genetically modified tumour models to identify the genes through which transcriptional regulators control differentiation of cytotoxic CD4+ T cell precursors. We will also define the nature of a checkpoint that prevents acquisition of cytotoxic function by precursor cells in untreated tumours. Finally, we will determine whether these regulatory mechanisms can be targeted to promote cytotoxic CD4+ T cell function and tumour immunity.This work will provide knowledge of the factors that control cytotoxic CD4+ T cell function and identify targets through which the activity of these cells can be harnessed in patients.